Microparticulate surgical adhesive

ABSTRACT

Flowable polymeric microparticulate surgical adhesive formulations are provided which can be activated at the site of the repair to produce cohesive material with tissue bonding properties to adjacent tissues. The formulation may be activated at the site of repair by mechanical shear forces, heat, ultrasound, UV, or other site.

BACKGROUND OF THE INVENTION

[0001] The invention relates to surgical adhesives, and in particular toadhesives which are formed by combination or reaction of theircomponents (hereinafter, “activated”) at the wound site.

[0002] Surgical adhesives have long been of interest for reconstructingtissues due to the ease of applicability and combined mechanicalsecurement and sealing function. Early use of a fibrin based adhesive,while totally biodegradable, was compromised by poor adhesive strengthespecially over time as enzyme degradation rapidly depolymerized thefibrin. Modern forms of fibrin adhesives incorporate enzyme inhibitorsnot only for practical workability, but to retard in-vivo degradationand loss of strength as described in U.S. Pat. No. 4,298,598. Still,these fibrin adhesives require the mixing of two components with longreconstitution times and demonstrate limited and variable working timebefore setting. In addition, the use of human pooled blood in theseproducts has raised concern regarding potential viral contamination andtransmission.

[0003] Synthetic adhesive systems, such as the cyanoacrylates andcyanobutylates have high adhesive strength, but have poor degradationproperties, with toxic byproducts such as formaldehyde being formed.Further, these materials are mechanically stiff and have poorintegration properties with healing tissues. The cyanoacrylate typeadhesive systems incorporate almost pure monomer which is initiated bywater to form a high strength polymer. The rapidly setting adhesive isdifficult to apply in some cases, especially in endoscopic use where theadhesive can set within the catheter lumen. Synthetic prepolymerapproaches such as described in U.S. Pat. No. 4,804,691 may utilizebiodegradable polymer components, but often rely on toxic componentssuch as isocyanates and metal catalysts. Small amounts of toxicity mayhave adverse effect on the critical tissue to adhesive interface of asurgical adhesive.

[0004] Collagen and gelatin based adhesive solutions have beeninvestigated. Early clinical work with thegelatin-resorcinol-formaldehyde adhesive showed problems with tissuecompatibility to the chemical agents and the cumbersome preparation ofthe adhesive. The use of a more toxicologically compatible collagensolution as described in EPA 0466383A1 requires heating of a collagensolution to partially transform it to gelatin. When applied heated ontothe tissues, the material cools to form a bond. In this case theadhesive is only held together by chain entanglement of thecollagen/gelatin chains, providing limited mechanical strength which iseasily disrupted during subsequent hydration and enzymatic action.Stability of the adhesive material at higher solids content was aperformance limitation.

[0005] A method described in U.S. Pat. No. 5,156,613 describes the useof a solid collagen filler material which is applied to tissues while anenergy source heats both the tissues and the filler material as a tissuewelding aid. The denaturation of the tissues and filler, upon coolingprovides a mechanical bond. While the approach utilizes high solidscontent adhesive, essentially a solid, the resultant adhesive materialis held together by chain entanglement of the collagen/gelatin chains,limiting mechanical strength and biodegradation resistance. In addition,the inherent damage to underlying tissues of tissue welding approachesin general may prevent use on or near sensitive tissues such as fragilevasculature, nervous tissue, ocular tissue, and areas of cosmeticconcern such as the face and neck. A similar approach is described inU.S. Pat. No. 5,209,776 where peptides such as collagen and albumin aremixed with either a polysaccharide or polyalcohol to form a viscoussolution which can be used as a sealant or coating. As the coating hasno material integrity, it is a weak flowable gel as described, with theprimary utility as a adjuvant to tissue welding techniques.

SUMMARY OF THE INVENTION

[0006] The present invention describes novel tissue adhesives comprisinga flowable polymeric microparticulate formulation which can be siteactivated to produce a cohesive material with tissue bonding propertiesto adjacent tissues. When activated, the material can be used to jointissues, seal tissue junctions, act as an injectable embolization agent,augment tissues and reinforce organ walls. The use of microparticulatesallows facile applicability as a powder or paste to tissues, with themicroparticles able to flow into the tissue crevices and set into theappropriate conformation.

[0007] It is an object of the invention to provide a high solids contentsurgical adhesive which provides total biodegradability, high mechanicalintegrity, and activation at the delivery site or wound, whichalleviates the problem of delay of application after mixing reactivecomponents.

[0008] Further objects are to provide a formulation for flowablesystems, to prevent damage to contacting tissues during application ofthe adhesive and biodegradation, to control the degradation rate of theadhesive, and to provide tissue ingrowth features in an adhesive toprovide a gradual load transfer to the healing tissues.

BRIEF DESCRIPTION OF THE DRAWING

[0009]FIG. 1 shows the activation of the surface of microparticles toform a solid material by polymer bridging.

[0010]FIG. 2 shows the activation of a polymerization mechanism by themixing of encapsulated reagents A and B to form a product C.

[0011]FIG. 3 shows the formation of a material with channels formed byactivation of a particulate polymer composition.

[0012]FIG. 4 shows activation of a flowable microparticulate formulationat the tip of a catheter with heat generating elements, D, to deliver amolten polymer adhesive.

[0013]FIG. 5 shows activation of a flowable microcapsule formulation atthe tip of a catheter with a rotating outer shaft, E, to spin a rotor,F, in the flow path to mechanically disrupt the microcapsules anddeliver an initiated adhesive.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The microparticulate adhesive comprises biodegradable componentsto allow for natural degradation and progressive incorporation withnewly formed tissue. This is particularly important for the clinicalsuccess of a surgical adhesive as rapid mechanical failure of theadhesive may lead to clinical problems. Preferred components arebiodegradable polymers including biopolymers such as collagen, gelatin,elastin, hyaluronic acid, and fibrin; synthetic degradable polymers suchas poly lactic/glycolic acid polymers and copolymers,polyhydroxybuterate, and polycaprolactone; and biological polymerizationcomponents such as fibrinogen and factor XIII.

[0015] Biopolymers such as collagen and gelatin in particular provide aprogressive degradation and load transfer to the healing tissues whichwould be preferred for clinical efficacy. The tissue integration of thesurgical adhesive with the healing tissues may be further promoted bythe formation of a porous structure by the microspheres in-situ, therebyallowing tissue ingrowth and mechanical interlocking. Other components,such as growth factors and chemotactic agents, may also be incorporatedinto the adhesive to further increase tissue incorporation and theperformance of the tissue repair.

[0016] The use of insoluble microparticles in a solvent mixture greatlyreduces viscosity and allows the use of a very high solids contentformulation that is flowable. For example, a typical collagen or gelatincomposition can achieve solids contents up to approximately 10 to 20weight % before the viscosity of the polymer increases to form anon-flowable solid. By constraining the polymer into discreet, insolublemicroparticles and preventing full polymer mobility, flowable solidscontents of approximately 50 weight % can be achieved. Since the solventvehicle in a polymeric adhesive, such as water, does not participate informing a structural adhesive, it is important to maximize the amount ofstructural polymer that is delivered as an adhesive. Small amounts ofreactive adhesive components or flow enhancers, may be incorporated intothe solvent vehicle for the microparticles, especially if they are oflower molecular weight to prevent viscosity limitations.

[0017] The use of microparticles or microspheres not only allows highsolids content, flowable formulations, but also allows activatablecomponents to be packaged within hollow or surface coated constructssimilar to industrial one part adhesives. While the typicalencapsulation of a catalyst in an industrial one-part adhesive utilizesrigid, fracturable materials such as glass, silica, and rigidthermoplastics to enhance rupture efficiency, these types of materialsare not toxicologically acceptable for implantation in tissues. Thepresent invention utilizes microcapsules fabricated entirely frombiodegradable polymers that can are rupturable by careful control ofcapsule thickness, and, optionally, by use of chemical surfacestabilization. In one embodiment, hollow microspheres or microcapsulesare fabricated from biodegradable materials and packed with reactivecomponents such as synthetic or biological polymerization systems. Thereactive components may be isolated in discreet capsules, whichpolymerize to form an adhesive when the capsules are broken bymechanical shear and mixed, such as at the end of a delivery catheter.An illustration of this method is shown in FIG. 5. An example is thepackaging of fibrinogen in microcapsules with separate microcapsules ofthrombin. Upon mechanical rupture, the components react to form a fibrinadhesive. Similarly, reactive adhesive components may be packaged withinwater insoluble capsules and delivered in an non-aqueous solvent to beactivated in situ by hydration. Thus, by activation of the adhesive at acatheter tip at the tissue site, working time and pot lifeconsiderations are minimized and adhesive kinetics and ultimateproperties can be optimized.

[0018] Activation methods other than mechanical shear can be utilizedwith the microcapsules or microparticles. Heat can be used to flowand/or rupture the particles by tailoring the thermal transitionproperties of the particulate materials. An illustration of that methodis shown in FIG. 4. Both biopolymers and biodegradable syntheticpolymers have thermal transitions such as the glass transitiontemperature, which can be tailored for use as adhesive microparticles.Physical methods such as ultrasound can be used in a combinedmechanical/thermal activation method. Radio frequency and microwaveexcitation, while having some patient shielding concerns, may also beutilized to thermally activate or rupture the microparticles to initiatethe adhesive.

[0019] It is important that the activation of the microparticles triggerreactions which form physiologically stable linkages within theresultant material. Typical linkages used include covalent crosslinkseither formed chemically or enzymatically, strong ionic interactionssuch as chelation, strong hydrophobic interactions, or inter-chainentanglement of polymers. For high physical strength, covalentcrosslinking and/or chain entanglement are preferred. In the case ofchain entanglement alone, such as the application of a heat activatablethermoplastic polymer component, it is important that the glasstransition of the polymer be above physiological temperature to form astable material. Otherwise, the resultant material would lack materialintegrity within the body, as occurs with non-crosslinked gelatin, forexample, with a transition temperature of about 37° centigrade.

[0020] Besides rupturing the microparticles to release adhesivecomponents, the particles themselves may physically participate in theadhesive material. The microparticles or microcapsules are fabricatedfrom high strength degradable polymers with affinity for the adhesivecomponents. In a system where microcapsules are ruptured to mix andinitiate a chemical adhesive, the wall components will be incorporatedinto the final adhesive material, acting as particulate reinforcements,similar to glass filled polymers. The same structural properties whichallow the microcapsule to resist premature rupture during use can befurther tailored to provide structural reinforcement of the adhesivematerial, especially controllable by crosslinking the capsule materialfor the proper biodegradation rate.

[0021] In some cases, it may not be necessary or desired to rupture themicroparticles. By combining the microparticles with a flowablecomponent which can be set into a solid, or by activating the surface ofthe microparticles, polymer bridges between particles may be formed toprovide structural material from the joined particles, similar to asintered polymer. Suitable activation methods may be used, such as heatto activate a thermoplastic polymer component or coating of themicroparticles. Other particle bridging components include collagen andgelatin, which will flow upon controlled heating and can be furtherenhanced by a thermoplastic coating or chemical surface graft such aspolylactic/glycolic acid polymers. As a bridging component,non-encapsulated polymer or reactive components such as difunctionalepoxides reagents may be used to facilitate adhesive setting. Otherparticle bridging methods include optically activatable groups such asacrylate functional materials which may be incorporated onto themicroparticles or formulated as a non-encapsulated component.

[0022] When significant portions of microparticles remain at leastpartially intact, the formation of channels of microparticles occur inthe material. Degradable microparticles may be used which to rapidlydegrade and form a porous network during biodegradation allowing tissueingrowth and progressive load transfer to the healing tissues, which isideal for preventing failure of the surgical adhesive repair.

[0023] The degradable microparticles may be fabricated by many availablemethods. Dry materials can be pulverized and sieved to produce irregularsolid particles of selected size range. Irregular particles, whilesimple to fabricate, tend to pack and clog during flow at high solidscontents. Microspheres, with a smooth outer surface have less tendencyto interlock with other particles, allowing for increased solids contentof a flowable formulation. Microspheres can be fabricated by a varietyof method including spray drying, coacervation/emulsion methods, anddroplet coagulation. In a preferred method for making hollowmicrospheres, a limited amount of cross-linking agent can be applied tosolid microspheres, then the cross-linking reaction is quenched. Theuncrosslinked centers may be extracted with a suitable solvent whichswells the cross-linked shell and dissolves the uncrosslinked centers.

[0024] Polymers in particular lend themselves to microspherefabrication. Polymeric microspheres may be further tailored afterfabrication by chemical crosslinking to control solubility andbiodegradation properties, and also chemically grafted or coated forchemical activation. Microspheres with hollow cavities may be used toisolate reactive adhesive components. Such microcapsules may be formedwith single or multiple cavities by methods such as interfacialdeposition, spray drying over a removable core, and the like. To packagethe reactive components, they may be formed into particles and coatedduring fabrication into microspheres. Alternatively, some reactivecomponents of low molecular weight may be incorporated by swelling theprefabricated microcapsules with a solution of the component andallowing for diffusion into the microcapsule interior.

[0025] It is preferred that the biodegradable microparticles have anactivatable mechanism to allow in-situ formation of a cohesive material.Heat can be used to fuse the microparticulate surfaces together with thedegree controlled by the microparticle surface composition and thermaltransition properties. In one method, gelatin particles are fusedtogether to form a cohesive mass upon heating at the end of a cathetertip. The gelatin thermal transition may be altered by the selection ofthe gelatin molecular weight, degree of deamidation, the type and extentof side chain modifications, and the degree of chemical crosslinkingwith difunctional chemical agents such as dialdehydes and diisocyanatesor peptide crosslinking agents such as carbodiimides. Less crosslinkedmaterials show lower temperatures needed for flowing of the particulatesinto a cohesive mass. The use of a thermoplastic synthetic polymer suchas polylactides/glycolides co-formulated in the adhesive increasesstrength and provides a multiphased structure to the heat activatedadhesive. The physical properties of such polymers may be selected ortailored by molecular weight, copolymer content, and plasticizercontent. In one embodiment, thermoplastic degradable polymers such aspolylactides, polyglycolides and glycolide/lactide copolymers, andlactone polymers may be coated or covalently grafted to the surface of aprotein microsphere, with the resulting microspheres having thermalbonding properties. Additional material stability can be achieved by theuse of a heat activatable crosslinking component, such as a difunctionalepoxide. Suitable chemical forms include diepoxide functionalpolyethylene glycols and polypropylene glycols, with activationoccurring at temperatures ranging from room temperature to approximately100 degrees C while demonstrating suitable toxicology.

[0026] Another method of activation is the use of light initiatedpolymerization of co-formulated monomers or activatable crosslinkers. Inone embodiment, the activatable crosslinkers are chemically grafted tothe surface of the biodegradable microparticles to promote high materialintegrity. Acrylate chemical functionality may be grafted onto gelatinmicrospheres for light activated polymerization of a particle bridgingcomponent such as acrylate and vinyl terminated polymers. Anillustration of surface bridged particles is shown in FIG. 1.

[0027] Another method of activation is the mechanical disruption ofhollow microspheres to allow mixing of reactive components. Anillustration of such a method is shown in FIG. 2. For a biologicaladhesive, for example, fibrinogen and factor XIII formulations form auseful surgical adhesive system, although with intensive preparationrequired and short working time. However, the encapsulation of thefibrinogen in a biodegradable polymer shell and formulation with afactor XIII containing solution provides a formulation readily appliedwith a catheter incorporating a mechanical disruption/mixing tip. Upondispensing, there is initiation of the fibrin adhesive to form acohesive material. Materials having more rapid setting kinetics may beused since working time is short. Typically, a fibrin based adhesiveincorporates at least 80 units of factor XIII activity per gram offibrinogen and small amounts of plasminogen activator inhibitor to aidshelf life and extend working time, and protease inhibitor to increasein-situ residence time. With the encapsulation of either the factor XIIIor the fibrinogen monomer, or both, a one component activatablebiological adhesive is produced.

[0028] Similarly, a combination of a synthetic polymerization initiatorand monomer may be sequestered into microencapsulated materials foractivation upon mechanical disruption and mixing. Examples includepolyethylene glycol, polyethylene glycol/lactide or glycolidecopolymers, reacted with polyethylene glycol diisocyanate, or otherreactive difunctional agents. Cyanoacrylate monomer may bemicroencapsulated to prevent the initiation of polymerization by wateruntil delivered at the catheter tip, thereby preventing setting andblockage in the catheter lumen.

[0029] Furthermore, rapidly degradable microparticles may beincorporated into the adhesive. Upon degradation of such microparticleschannels or pores will be formed which are beneficial for tissuein-growth. An illustration of an adhesive with such channels is shown inFIG. 3.

[0030] The activation of the microparticulate adhesive can be performedat the surgical repair site by first dispensing the adhesive and thenactivating it with either light, heat, radio frequency, or other form ofenergy. For endoscopic use, a catheter with an activation mechanism atthe tip is preferred. A concentric heating element around the cathetertip provides activation that can be coordinated with the feeding of themicroparticles to dispense an activated adhesive. Similarly, forreactive adhesive systems where microcapsules are ruptured and mixed,small gear mechanisms, rotating blades, or narrow orifices providesuitable mechanical shear for activation. Small ultrasonic transducersmay be incorporated into a catheter, providing both mechanical andthermal energy to both rupture microcapsules and thermally activate thematerial. Similarly, for optical systems, a fiber optic incorporatedinto the catheter tip may provide suitable adhesive activation at thedispensing tip.

EXAMPLE 1

[0031] Gelatin/Hyaluronic Acid Microcapsules Activated by Heat

[0032] Biopolymer microcapsules were prepared containing dyed mineraloil by means of complex coacervation using the sodium salt of hyaluronicacid as the anionic polymer. The ratio of ingredients were as follows:gelatin, type A, 200 bloom  6 parts by wt hyaluronic acid, sodium salt 1 part water 100 parts mineral oil, dyed  25 parts

[0033] Aqueous dispersions of the polymers were prepared, mixed togetherand adjusted to pH of 6.75 while heating to 36 degrees C. Afteremulsification of the mineral oil into the dispersion, the pH was slowlyadjusted to 4.80 to stabilize the microcapsules. The resultingoil-containing microcapsules were retrieved by filtration and convertedto a free flowing powder by solvent exchange with isopropyl alcohol withsubsequent lyophilization.

[0034] The dyed mineral oil contained within the microspheres thusserving as an active agent analog, the pre-reactant component consistedof an aqueous slurry prepared at approximately 20% by weight andadjusted to a basic pH. Microscopic examination of the slurry revealeddiscrete multicore microcapsules uniformly dispersed in a water medium.The slurry was fed to the delivery site by a syringe pump and activatedat the tip of the assembly through a heated nozzle. The nozzle consistedof a brass tube spirally wrapped with heater wire, all under a layer offiberglass insulation. The nozzle temperature was adjusted by a Variacpower controller applied to the heater coil. The slurry was pumped atapproximately 20 ml/min, and heated to approximately 85 degrees C.Microscopic examination of the resulting material revealed that themicrocapsules had ruptured and dissolved, releasing the oil contentsfrom the protective gelatin shell.

EXAMPLE 2

[0035] Gelatin/Hyaluronic Acid Microcapsules Activated by Ultrasound

[0036] Gelatin microcapsules containing dyed mineral oil as previouslydescribed were prepared in accordance with the first example. A 20%aqueous slurry was prepared and adjusted to a basic pH. Using a HeatSystems model 2020XL ultrasonic generator with standard probe andmicrotip horn, the slurry was sonicated at a setting of 5 forapproximately 40 seconds. Microscopic examination of the resultingmixture revealed that the encapsulated oil had been released from theruptured polymer capsules.

EXAMPLE 3

[0037] Thrombin Based Adhesive Utilizing Encapsulated FibrinogenActivated Mechanically

[0038] Fibrinogen microspheres are prepared by coacervation of anaqueous dispersion emulsified into mineral oil. Slow dehydration withthe addition of cold isopropyl alcohol yields a fibrinogen microspherepreparation of approximately 50 micron diameter. The resulting particlesare isolated by centrifugation and washed in isopropyl alcohol and driedunder vacuum. The free flowing particles are then encapsulated with alight coating of polylactic acid by spray drying. The particles aresuspended in a methylene chloride dispersion of polylactic acid, in therange of 0.05 to 50 weight percent. The lower concentrations arepreferred to form a thin encapsulating shell. The resulting coatedmicrospheres are then formulated into a 30 weight percent slurry withphosphate buffer with thrombin or Factor XIII activity in the ratio ofapproximately 100 to 1000 units of Factor XIII activity per gram ofencapsulated fibrinogen. Upon passage of the flowable slurry through acatheter with a mechanical shearing tip, the fibrinogen is released andforms a cohesive gel-like material upon reaction with the thrombin.

EXAMPLE 4

[0039] Gelatin Particulate Based Adhesive Formulation Activated by Heat

[0040] A flowable gelatin slurry was prepared by first mixingpolyethylene glycol 400, glycerol, and water in the followingproportions: polyethylene glycol 400 0.75 grams glycerol 2.25 gramswater 1.00 grams

[0041] To this solution was added 3 grams of gelatin powder having agrain size no greater than approximately 500 microns to form a 40 weightpercent solids slurry. The slurry was fed to the delivery site using thenozzle system described in the first example. The slurry was pumped atapproximately 3 ml/min and heated to approximately 100 degrees C.Exiting the nozzle was a highly viscous, molten gelatin. Upon coolingthe material hardened into a cohesive rubbery mass.

EXAMPLE 5

[0042] Gelatin Microsphere Based Adhesive Formulation with In-SituCrosslinking

[0043] A gelatin adhesive formulation was prepared with the followingcomponents: gelatin microspheres, ˜25 to 50 micron diameter 250 mgpolyethylene glycol, dialdehyde, 3400 MW  50 mg deionized water  2 grams

[0044] The mixture was quickly mixed and allowed to set at roomtemperature. After one half hour, the material has become a firm gel.Incubation at 45 degrees C showed a stable gel, unlike thenon-crosslinked control sample which dissolved. Microscopic examinationshowed a cohesive mass of microspheres, bridged together to form thematerial.

EXAMPLE 6

[0045] Gelatin Particulate Based Adhesive Formulation with HeatActivated Crosslinking

[0046] A gelatin adhesive formulation was prepared with the followingcomponents: gelatin powder, grain size < 500 microns 9 gramspolyethylene glycol 400 2.25 grams glycerol 7.5 grams polyethyleneglycol, diepoxide, MW3400 200 mg

[0047] The components were stirred together to form a particulate slurryof approximately 47 weight % solids. With a syringe, the mixture wasextruded through a heating element with a 0.5 cm bore, heated toapproximately 140 degrees C. The extrudate was a uniform transparentamber color, indicating fusion of the gelatin material. Once cooled, thematerial exhibited a cohesive, rubbery properties. The material wasstable when placed in water heated to 40 degrees C for 17 hours,indicating crosslinking into a stable adhesive material.

EXAMPLE 7

[0048] Hollow Gelatin Microsphere with Thermoplastic Polymer Graft BasedAdhesive Formulation. Activated by Heat

[0049] Hollow gelatin microspheres were prepared by fabricating ˜50micron diameter gelatin microspheres by emulsion of a 200 bloom gelatindispersion into mineral oil. The microspheres were recovered afterprecipitation with cold isopropanol and surface crosslinked in a mixtureof 1,3 dimethylaminopropyl-3-ethylcarbodiimide hydrochloride at 0.67mg/ml in 1:14 volume ratio of water:acetone for 12 minutes at roomtemperature. The microsphere crosslinking was quenched with a chilled,acidified water:acetone solution, and washed two time by centrifugationin acetone. The microspheres were resuspended in deionized water andheated to 80 degrees C for 4 hours, after which the microspheres wereisolated by centrifugation. Approximately 21% of the original gelatinweight was remaining, indicating an extraction of the uncrosslinkedcenter. The resulting microspheres demonstrated a hollow morphology withvery thin walls when examined microscopically. The gelatin microsphereswere then washed in THF and grafted with caprolactone to form athermoplastic polycaprolactone coating, covalently attached to themicrosphere surface. Approximately 50 mg of the dried microspheres wereplaced in a reaction mixture containing the following components: 0.2 mltriethyl aluminum, 50% in toluene 2.0 grams caprolactone monomer 8.0grams tetrahydrofurane

[0050] The reaction was heated for approximately 5 hours at 40 degreesC. The microspheres were isolated from the reaction mixture bycentrifugation at 2400 rpm for 15 minutes. The microspheres were washed3 times in fresh THF solvent and recovered as dry, free flowingparticles. When heated on a glass slide at approximately 90 degrees C,the particles fused into a mass of aggregated microspheres. Undermicroscopy, the fused mass of material showed a reticulated morphology.

EXAMPLE 8

[0051] Gelatin Particulate Based Adhesive with Thermoplastic BindingAgent

[0052] A polymer dispersion of polycaprolactone (Solvay CAPA 650), 7.2 gin 30 ml of methylene chloride was prepared. A separate dispersion ofgelatin, 4.8 g of gelatin was dissolved with light heating into 11.2 mlof deionized water containing 1.6 g each of glycerol and PEG 400. Afinely divided emulsion was formed by mixing the two immisciblesolutions together with vigorous mixing. The viscous mixture was thenpoured on a glass plate, heated to 80 degrees C on a glass plate andallowed to dry at room temperature overnight. The material was thenheated to 80 degrees C to form a melt, and molded into cylindricalshapes approximately 8.5 cm long and 0.65 cm in diameter. The resultingflexible rod was then melted and extruded through a heating tube of 0.2cm diameter and heated to approximately 140 degrees centigrade. A moltenpolymer was dispensed which cooled into a very cohesive, flexiblematerial with an appearance similar to the starting material. A 0.134 gspecimen of the dispensed adhesive was placed in deionized water at 40degrees C for approximately 64 hours to simulate extraction of thegelatin particle component in-vivo. The specimen was then removed andallowed to dry. The weight of the specimen was 0.064 g, a reduction ofapproximately one half of the weight, which roughly corresponds to thegelatin and glycerol/PEG components. The specimen had become white, thecolor of the caprolactone polymer. Microscopic inspection of the sampleshowed that the gelatin had been dissolved to form a surface porosity,with both interconnected and non-interconnected pores through thematerial cross-section.

What is claimed is:
 1. A microparticulate surgical adhesive compositioncomprising biodegradable polymeric microparticles; which are activatablein-situ to form a high strength, cohesive material which isphysiologically stable.
 2. An adhesive composition according to claim 1which is activatable in-situ by rupturing of an impermeable outer shellor coating of said microparticles to initiate a chemical reaction toform said cohesive material.
 3. An adhesive composition according toclaim 1 which is activatable in-situ by fusion of said microparticles toform said cohesive material.
 4. An adhesive composition according toclaim 1 which is activatable in-situ to form said cohesive materialwhich comprise channels or pores for tissue integration.
 5. An adhesivecomposition according to claim 1 comprising a flowable slurry with aphysiologically compatible solvent.
 6. An adhesive composition accordingto claim 1 which is activatable by heat.
 7. An adhesive compositionaccording to claim 1 which is activatable by ultrasound energy.
 8. Anadhesive composition according to claim 1 which is activatable by radiofrequency or microwave energy.
 9. An adhesive composition according toclaim 1 which is activatable by light.
 10. An adhesive compositionaccording to claim 1 which is activatable by mechanical shear.
 11. Anadhesive composition according to claim 1 which further comprises aparticle bridging component.
 12. An adhesive composition according toclaim 1 which further comprises a coating or chemical graft on thesurfaces of said microparticles.
 13. An adhesive composition accordingto claim 1 which further comprises modified chemical surfaces of themicroparticles.
 14. An adhesive composition according to claim 1 whichfurther comprises growth factors or chemotactic factors.
 15. An adhesivecomposition according to claim 1 which further comprises wound healingagents, anti-infective agents or anti-inflammatory agents.
 16. Anadhesive composition according to claim 1 which further comprises hollowmicroparticles.
 17. An adhesive composition according to claim 1 whichfurther comprises coated components which are ruptured to initiateformation of adhesive.
 18. An adhesive composition according to claim 1which further comprises collagen or gelatin microparticles.
 19. Anadhesive composition according to claim 1 which further comprisesfibrinogen and factor XIII.
 20. An adhesive composition according toclaim 1 which further comprises a biodegradable thermoplastic polymer.21. A flowable adhesive composition according to claim 1 having a solidscontent greater than 20 weight percent.
 22. A method for the securementand sealing of tissue by the site activation of a biodegradablemicroparticle composition comprising biodegradable polymericmicroparticles, which are activatable in-situ to form a high strength,cohesive material which is physiologically stable.
 23. A method for thesecurement and sealing of tissue by the introduction of a microparticlecomposition comprising biodegradable polymeric microparticles, which areactivatable in-situ to form a high strength, cohesive material which isphysiologically stable through an apparatus which activates saidcomposition as it is delivered to the target tissues.
 24. A method forthe embolization of biological vessels by the introduction of amicroparticle composition comprising biodegradable polymericmicroparticles, which are activatable in-situ to form a high strength,cohesive material which is physiologically stable through a catheterwhich activates said composition as it is delivered to the targettissues.
 25. A method for fabricating hollow microcapsules by theintroduction of limited crosslinking agent to surfaces of microspheres,quenching the crosslinking reaction, and extracting the centers of themicrospheres with a solvent which swells the crosslinked shell andallows extraction of the uncrosslinked centers.